The present invention relates to new heterocyclic derivatives having an:,inhibitory activity on calpains and/or a trapping activity on reactive oxygen species (ROS""s). The invention also relates to methods for their preparation, pharmaceutical preparations containing them and their use for therapeutic purposes, in particular as inhibitors of calpains and selective or non-selective ROS traps.
Given the potential role of calpains and ROS""s in physiopathology, the new derivatives according to the invention can produce beneficial or favourable effects in the treatment of pathologies involving these enzymes and/or these radicular species, and in particular:
inflammatory and immunological diseases such as for example rheumatoid arthritis, pancreatitis, multiple sclerosis, inflammation of the gastro-intestinal tract (ulcerative or non-ulcerative colitis, Crohn""s disease),
cardiovascular and cerebrovascular diseases including for example arterial hypertension, septic shock, cardiac or cerebral infarctions of ischemnic or hemorrhagic origin, ischemia as well as disorders linked to platelet aggregation,
disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned trauma to the brain or spinal cord, sub-arachnoid haemorrhages, epilepsy, ageing, senile dementia, including Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, peripheral neuropathies,
osteoporosis,
muscular dystrophies,
proliferative diseases such as for example atherosclerosis or recurrence of stenosis,
cataracts,
organ transplants,
auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes and its complications, multiple sclerosis,
cancer,
all the pathologies characterized by an excessive production of ROS""s and/or activation of calpains.
In all these pathologies, there is experimental evidence demonstrating the involvement of ROS""s (Free Radic. Biol. Med. (1996) 20, 675-705; Antioxid. Health. Dis. (1997) 4 (Handbook of Synthetic Antioxidants), 1-52) as well as the involvement of calpains (Trends Pharmacol. Sci. (1994) 15, 412419; Drug News Perspect (1999) 12, 73-82). For example, cerebral lesions associated with cerebral infarction or experimental cranial trauma are reduced by antioxidants (Acta Physiol. Scand. (1994) 152, 349-350; 1. Cereb. Blood Flow Metabol. (1995) 15, 948-952; J Pharmacol Exp Ther (1997) 2, 895-904) as well as by inhibitors of calpains (Proc Natl Acad Sci USA (1996) 93, 3428-33; Stroke, (1998) 29, 152-158; Stroke (1994) 25, 2265-2270).
A subject of the present invention is therefore compounds of general formula (I) 
in which
R1 represents a hydrogen atom, an xe2x80x94OR3, xe2x80x94SR3, oxo or cyclic acetal radical,
in which R3 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R4 and R5 represent, independently, a hydrogen atom or an alkyl radical, or R4 and R5 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R2 represents a hydrogen atom, an alkyl, aryl or aralkyl radical, the aryl group being optionally substituted by one or more identical or different radicals chosen from: xe2x80x94OR6, xe2x80x94NR7R8, halogen, cyano, nitro or alkyl,
in which R6, R7 and R8 represent, independently, a hydrogen atom, an alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical;
A represents
either an A1 or Axe2x80x21 radical 
xe2x80x83in which R9, R10, R11, R12, R13 represent, independently, a hydrogen atom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or xe2x80x94NR15R16 radical,
R15 and R16 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR17 group, or R15 and R16 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R17 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR18R19 radical,
R18 and R19 represent, independently, a hydrogen atom or an alkyl radical, or R18 and R19 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R14 represents a hydrogen atom, an alkyl radical or a xe2x80x94COR20 group,
R20 represents a hydrogen atom, an alkyl, alkoxy, aryl, aralkyl, heterocycloalkyl or xe2x80x94NR21R22 radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R21 and R22 represent, independently, a hydrogen atom or an alkyl radical, or R21 and R22 together with the nitrogen atom to which they are, attached form an optionally substituted heterocycle,
W represents a bond, O or S or also an xe2x80x94NR23 radical, in which R23 represents a hydrogen atom or an alkyl radical;
or an A2 radical 
xe2x80x83in which
R24, R25 and R26 represent, independently, a hydrogen, a halogen, the OH or SR27 group, an alkyl, alkenyl, alkoxy radical or an xe2x80x94NR28R29 radical,
R27 represents a hydrogen atom or an alkyl radical,
R28 and R29 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR30 group, or R28 and R29 form together with the nitrogen atom to which they are attached an optionally substituted heterocycle,
R30 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR31R32 radical,
R31 and R32 represent, independently, a hydrogen atom or an alkyl radical, or R31 and R32 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
Q represents xe2x80x94OR33, xe2x80x94SR33, xe2x80x94NR34R35 or an aryl radical substituted by one or more identical or different substituents chosen from: halogen, the OH group, an alkyl, alkoxy, cyano, nitro or xe2x80x94NR15R16 radical,
R33 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R34 and R35 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COxe2x80x94R36 radical, or together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R36 representing an alkyl radical;
or an A3 radical 
xe2x80x83in which R37 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
T represents a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2;
or an A4 radical 
in which R38 represents a hydrogen atom, an alkyl, xe2x80x94(CH2)qxe2x80x94NR39R40 or aralkyl radical, the aryl group being optionally substituted by one or more identical or different substituents chosen from: OH, alkyl, halogen, nitro, alkoxy or xe2x80x94NR39R40,
q being an integer comprised between 2 and 6;
or an A5 radical 
xe2x80x83in which Rxe2x80x238 and Rxe2x80x338 represent independently a hydrogen atom, nitro, xe2x80x94NRxe2x80x239Rxe2x80x240, an alkyl or arylalkyl radical, the aryl group being optionally substituted by one or more identical or different substituents chosen from: OH, the alkyl, halogen, nitro, alkoxy or xe2x80x94NR39R40 radicals,
Rxe2x80x239, Rxe2x80x240, R39 and R40 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR41 group, or R39 and R40 or Rxe2x80x239 and Rxe2x80x240 together with the nitrogen atom form an optionally substituted heterocycle,
R41 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR42R43 radical,
R42 and R43 represent, independently, a hydrogen atom or an alkyl radical, or R42 and R43 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
T representing a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2,
or finally an A6 radical 
in which R44 represents a hydrogen atom, the OH group or an alkyl or alkoxy radical;
X represents xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94(CHn)2xe2x80x94COxe2x80x94, xe2x80x94N(45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94NHxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94Sxe2x80x94(CH2)n,xe2x80x94COxe2x80x94 or xe2x80x94Zxe2x80x94COxe2x80x94;
D represents a phenylene radical optionally substituted by one or more identical or different radicals chosen from alkyl, alkoxy, OH, nitro, halogen, cyano, or carboxyl optionally esterified by an alkyl radical;
Z represents a heterocycle,
R45 represents a hydrogen atom or an alkyl radical,
R46 and R47 represent, independently, a hydrogen atom, an alkyl, aryl or aralkyl radical the alkyl and aryl groups of which are optionally substituted by one or more identical or different substituents chosen from: the OH, xe2x80x94SH, halogen, nitro, alkyl, alkoxy, alkylthio, aralkoxy, aryl-alkylthio, xe2x80x94NR48R49 and carboxyl group optionally esterified by an alkyl radical;
R48 and R49 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR50 group, or R48 and R49 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R50 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR51R52 radical,
R51 and R52 represent, independently, a hydrogen atom or an alkyl radical, or R51 and R52 together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;
n being an integer comprised between 0 and 6;
Y represents xe2x80x94(CH2)pxe2x80x94, xe2x80x94C(R53R54)xe2x80x94(CH2)pxe2x80x94, xe2x80x94C(R53R54)xe2x80x94COxe2x80x94;
R53 and R54 represent, independently, a hydrogen atom, an alkyl radical, an aralkyl radical the aryl group of which is optionally substituted by one or more identical or different substituents chosen from: the OH, halogen, nitro, alkyl, alkoxy, xe2x80x94NR55R56 group,
R55 and R56 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR57 group, or R55 and R56 together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle,
R57 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR58R59 radical,
R58 and R59 represent, independently, a hydrogen atom or an alkyl radical, or R58 and R59 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle;
p being an integer comprised between 0 and 6;
Het represents a heterocycle,
as well as the addition salts with mineral and organic acids or with mineral and organic bases of said compounds of general formula (I),
with the exception of the compounds of formula (I) in which when Het represents tetrahydrofuran or tetrahydropyran, R1 represents the OR3 radical with R3 representing a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl radical the heterocycloalkyl radical of which is connected by a carbon atom, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical, R2 represents a hydrogen and Y represents the xe2x80x94(CH2)pxe2x80x94radical with p=0, then X does not represent xe2x80x94COxe2x80x94N(R45)xe2x80x94C(R46R47)xe2x80x94COxe2x80x94 with R45=R46=H.
In certain cases, the compounds according to the present invention can comprise asymmetrical carbon atoms (of xe2x80x9cRxe2x80x9d or xe2x80x9cSxe2x80x9d configuration). As a result, the present invention includes the enantiomeric, diastereoisomeric forms and all combinations of these forms, including the xe2x80x9cRSxe2x80x9d racemic mixtures. In an effort to simplify matters, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric (or diastereoisomeric) forms and their mixtures are represented.
By alkyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms such as, for example, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. The alkoxy radicals can correspond to the alkyl radicals indicated above such as for example the methoxy, ethoxy, propyloxy or isopropyloxy radicals but also linear, secondary or tertiary butoxy. Similarly the alkylthio radicals can correspond to the alkyl radicals indicated above such as for example methylthio or ethylthio.
By alkenyl, unless otherwise specified, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond). By halogen, is meant the fluorine, chlorine, bromine or iodine atoms.
By aryl, is meant a carbocyclic or heterocyclic system comprising at least one aromatic ring, a system being called heterocyclic when at least one of the rings composing it comprises a heteroatom (O, N or S). As an example of a carbocyclic aryl radical, there can be mentioned phenyl or naphthyl. As an example of a heterocyclic aryl radical (or heteroaryl), there can be mentioned thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidyl, benzothienyl, benzofuryl and indolyl.
The term heterocycle (or heterocycloalkyl), represented for example by the Het or Z radicals, preferably represents a saturated or unsaturated, mono or bicyclic heterocycle, comprising 1 to 5 heteroatoms chosen from O, S, N. The nitrogen atom can optionally be substituted by a radical chosen from: alkyl, aryl, aralkyl and alkylcarbonyl. As an example of a saturated heterocycle, there can be mentioned tetrahydrofuran, tetrahydropyran, oxetane, oxepane, tetrahydrothiophene, tetrahydrothiopyran, thietane, pyrrolidine, piperidine, azetidine, 1,3-dioxane, 1,3-dioxolane, 1,3-dithiolane, 1,3-dithiane, 1,3-oxathiolane, 1,3-oxazolidine, 1,3-imidazolidine or 1,3-thiazolidine. As an example of an unsaturated heterocycle, there can be mentioned: thiophene, furan, pyrrol, imidazole, pyrazole, isothiazole, thiazole, isoxazole, oxazole, pyridine, pyrazine, pyrimidine, benzimidazole, benzofun, benzopyran, 1,3-benzothiazole, benzoxazole, quinoline.
The arylalkyl (or aralkyl) radicals designate the radicals in which the aryl and alkyl radicals respectively are as defined above such as for example benzyl, phenylethyl or naphthylmethyl. The aralkoxy (aryl-alkoxy) radicals designate the radicals in which the aryl and alkoxy radicals respectively are as defined above such as for example benzyloxy or phenylethoxy. The arylalkylthio radicals designate the radicals in which the aryl and alkylthio radicals respectively are as defined above such as for example benzylthio.
The alkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl or aralkylcarbonyl radicals designate the radicals in which the alkyl, heterocycloalkyl, aryl and aralkyl radicals respectively have the meaning indicated previously.
In the case of radicals of formula xe2x80x94NRiRj where Ri and Rj together with the nitrogen atom to which they are attached form an optionally substituted heterocycle, the heterocycle is preferably saturated and comprises 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms. Said heterocycle can be, for example, the azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine ring. Said heterocycle can be substituted by one or more identical or different substituents chosen from the hydroxy group, an alkyl, aryl, aralkyl or alkoxy radical or a halogen atom.
A more particular subject of the invention is the compounds of formula (I) as defined above, in which Het represents a monocyclic radical containing 1 to 2 heteroatoms chosen from O and N, and preferably a radical corresponding to the tetrahydrofuran, dioxolane, pyrrolidine, 1,3-oxazolidine ring, and R1 represents the hydrogen atom, the xe2x80x94OR3 or oxo radical.
A more particular subject of the invention is the compounds of formula (I) as defined above, in which X represents xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94NHxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94C(R46R47)xe2x80x94COxe2x80x94 or xe2x80x94Zxe2x80x94COxe2x80x94,
and preferentially when R45 and R47 represent the hydrogen atom, R46 represents the hydrogen atom, an alkyl or phenyl radical, D represents the phenylene radical and Z represents the thiazole radical.
A more particular subject of the invention is also compounds of formula (I) as defined above, in which R2 represents a hydrogen atom or an aralkyl radical, and preferably the benzyl radical.
A more particular subject of the invention is also compounds of formula (I) as defined above, in which A represents
either A1 with W representing the sulphur atom,
or Axe2x80x21
or A2 with R24, R25 and R26 which represent, independently, a hydrogen or an alkyl radical and Q which represents xe2x80x94OR33,
or A3 with T representing the xe2x80x94(CH2)2xe2x80x94radical;
or A4 with T representing the xe2x80x94(CH2)xe2x80x94radical,
and preferably the radicals of formula 
A more particular subject of the invention is also the compounds described hereafter in the examples and preferably the products corresponding to the following formulae:
(2R)-6-hydroxy-N-[(3S)-2-hydroxytetrahydro-3-furayl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;
N-1-(4-anilinophenyl)-N-4-[(3S)-2-hydroxytetrahydro-3-furanyl]succinamide;
(3S)-3-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}tetrahydro-2-furanyl acetate;
N-1-(4-anilinophenyl)-N-4-[(1S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl]succinamide;
N-1-(4-anilinophenyl)-N-3-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenylmalonamide;
3-(4-anilinoanilino)tetrahydro-2-furanol;
N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)-amino]pentanoyl}amino)tetrahydro-2-furanyl acetate;
N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;
N-[4-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;
N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl pivalate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)-tetrahydro-2-furanyl3,3dimethylbutanoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl benzoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl phenylacetate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl (2S)-2-(dimethylamino)-3-phenylpropanoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl 4-morpholinecarboxylate;
N-{(1S)-3-methyl-1-[(3-oxo-1-pyrrolidinyl)carbonyl]butyl}-10H-phenothiazine-2-carboxanmide;
2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]acetamide;
N1-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenyl-N3-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;
N-(2-anilinophenyl)-Nxe2x80x2-[(3S)-2-hydroxytetrahydro-3-furanyl]urea;
Nxe2x80x2-[(3S)-2-hydroxytetrahydro-3-furanyl]-N2-(1-propyl-2,3-dihydro-1H-indol-5-yl)ethanediamnide;
(2R)-N-[(1S)-1-(1,3-dioxolan-2-yl)-2-phenylethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;
N-[(3S)-2-hydroxytetrahydro-3-furanyl]-5-indolinecarboxamide.
The compounds of formula I according to the invention can be prepared via several synthesis routes according to the definition of the variable groups.
The compounds of general formula (I) in which Het represents the tetrahydrofuran ring and Y represents the xe2x80x94(CH2)p radical, can be prepared according to the following diagram: 
in which A, X, R2 and R3 are as described above, by condensation of the acids of general formula (II) on the amines of general formula(III), under standard conditions for peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)) in order to produce the intermediate carboxamides of general formula (IV). The lactonic ring of the intermediates of general formula (IV) is then reduced using a reducing agent such as, for example, diisobutylaluminium hydride (DIBAL), in an inert solvent such as, for example, THF or CH2Cl2, at a temperature varying from 0 to xe2x88x9278xc2x0 C. The lactol derivative of general formula (Ixe2x80x2) obtained in this 1 s way can be acylated using, for example, an acid chloride (R3xe2x80x94Cl) or an acid anhydride (acetic anhydride, benzoyl chloride, etc.) in the presence of a base such as, for example, triethylamine, in an inert solvent such as for example CH2Cl2 in order to produce the compound of general formula (I).
The compounds of formula (I) in which Het represents the pyrrolidinyl radical and Y represents xe2x80x94C(R53R54)xe2x80x94COxe2x80x94, R53 and R54 being as defined above, can be prepared according to the following diagram: 
in which A, X and R2 are as described above, by condensation of the acids of general formula (V) on the amines of general formula (VI) (J. Med. Chem. (1992) 35 (8), 1392-1398) under standard conditions for peptide synthesis, as described previously, in order to produce the compounds of general formula (Ixe2x80x2). The optional deprotection of the ketone function is then carried out according to the methods described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)), in order to produce the compounds of general formula (I).
The compounds of formula (I) in which Het represents the 1,3-dioxolane, 1,3-dioxane, 1,3-dithiane, 1,3-dithiolane, 1,3-oxathiolane, 1,3-oxazolidine, 1,3-imidazolidine or 1,3-thiazolidine ring, and Y represents xe2x80x94C(R53R54)xe2x80x94COxe2x80x94, R53 and R54 being as defined above, can be prepared according to the following diagram: 
in which A, X and R2 are as described above and V and Vxe2x80x2 represent independently N, O or S, by condensation of the acids of general formula (II) described previously, on the commercial amino-esters of general formula (VII), under the standard conditions for peptide synthesis described previously, in order to produce the intermediates of general formula (VIII). Reduction of the carboxylic ester using a reducing agent such as, for example, DIBAL, in an inert solvent such as, for example, THF or CH2Cl2, at a temperature varying from 0 to xe2x88x9278xc2x0 C., leads to the aldehydes of general formula (IX). Conversion of the aldehyde to a heterocycle is carried out according to the methods in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)).
The compounds of formula (I) in which Het represents the oxazolidine ring can be prepared according to the following diagram: 
in which A, X, Y, R2 and R3 are as described above, by condensation of the acids of general formula (V) described previously, with the commercial amino-esters of general formula (X) under the peptide synthesis conditions described previously. The esters of general formula (XI) obtained intermediately are then saponified in order to produce carboxylic acids of general formula (XII), which by heating in the presence of paraformaldehyde and of an acid such as, for example, PTSA, while continually trapping the water formed during the reaction using a device of Dean-Stark type, lead to the oxazolidinones of general formula (XIlI). These are then reduced using a reducing agent such as, for example, DIBAL, in an inert solvent such as, for example, THF or CH2Cl2, at a temperature varying from 0 to xe2x88x9278xc2x0 C. in order to produce oxazolidine derivatives of general formula (Ixe2x80x2). The compounds of general formula (Ixe2x80x2) obtained in this way can be acylated using, for example, an acid chloride (R3xe2x80x94Cl) or an acid anhydride (acetic anhydride, benzoyl chloride, etc.) in the presence of a base such as, for example, triethylamine, in an inert solvent such as for example CH2Cl2 in order to produce the compounds of formula (I).
The compounds of general formula (I) in which Het represents the tetrahydrofuran ring, X represents the xe2x80x94(CH2)nxe2x80x94 radical (n=0) and Y represents the xe2x80x94(CH2)pxe2x80x94 radical (p=0), can also be prepared according to the following diagram: 
in which A, R2 and R3 are as described above, by nucleophilic substitution of the halogen of the lactones of general formula (XV) using the amines of general formula (II.1), while heating the reaction mixture to a temperature varying from 50 to 110xc2x0 C. in an inert solvent such as for example, acetonitrile or DMF, for a duration varying from 30 minutes to 5 hours, in order to produce the intermediates of general formula (XV). Reduction of the lactone function followed by acylation of the lactol of general formula (Ixe2x80x2) are carried out under the conditions described previously.
The compounds of general formula (I) in which Het represents the tetrahydrofuran ring, X represents the xe2x80x94N(R45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94 radical (n=0) and Y represents the xe2x80x94CH2)pxe2x80x94 radical (p=0) are ureas which can be prepared according to the following synthesis diagram: 
in which A, R2 and R3 are as described above, by condensation of the amines of general formula (II.1) with the amines of general formula (III) in the presence of triphosgene and of a base such, as, for example, diisopropylethylamine in an inert solvent such as dichloromethane according to an experimental protocol described in J. Org. Chem. (1994) 59 (7), 1937-1938. The lactonic ring of the ureas of general formula (XVI) is then reduced and modified under the experimental conditions described previously in order to produce the compounds of general formula (I).
The compounds of the present invention have useful pharmacological properties: they have an inhibitory activity on calpains and/or a trapping activity on reactive oxygen species.
The compounds of the present invention can thus be used for different therapeutic applications. They can produce beneficial or favourable effects in the treatment of pathologies where these enzymes and/or these radicular species occur.
These properties render the products of formula I suitable for pharmaceutical use. A subject of the present Application is also, as medicaments, the products of formula I as defined above, as well as the addition salts with pharmaceutically acceptable mineral or organic acids or mineral or organic bases of said products of formula I, as well as the pharmaceutical compositions containing, as active ingredient, at least one of the medicaments as defined above.
The invention therefore relates to pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable addition salt of the latter, in combination with a pharmaceutically acceptable support. The pharmaceutical composition can be in the form of a solid, for example, powders, granules, tablets, gelatin capsules or suppositories. The appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water, added to pharmaceutically acceptable oils or greases. Sterile liquid compositions can be used for intramuscular, intraperitoneal or sub-cutaneous injections and sterile compositions can also be administered intravenously.
Certain compounds of general formula I described previously are covered by the Application EP 641800. The compounds of this Application have an inhibitory activity on cathepsine L which is different from the inhibitory activity on calpains and/or the trapping activity on reactive oxygen species.
A subject of the invention is therefore also the use of compounds of formula (Ia) as defined above, 
in racemic, enantiomeric, diastereoisomeric form or all combinations of these forms, in which
Ra1 represents a hydrogen atom, an xe2x80x94OR3, xe2x80x94SR3, oxo or cyclic acetal radical,
in which R3 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R4 and R5 represent, independently, a hydrogen atom or an alkyl radical, or R4 and R5 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
Ra2 represents a hydrogen atom, an alkyl, aryl or aralkyl radical, the aryl group being optionally substituted by one or more identical or different radicals chosen from: xe2x80x94OR6, xe2x80x94NR7R8, halogen, cyano, nitro or alkyl,
in which R6, R7 and R8 represent, independently, a hydrogen atom, an alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical;
Aa represents
either an A1 or Axe2x80x21 radical 
in which R9, R10, R11, R12, R13 represent, independently, a hydrogen atom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or xe2x80x94NR15R16 radical,
R15 and R16 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR17 group, or R15 and R16 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R17 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR18R19 radical,
R18 and R19 represent, independently, a hydrogen atom or an alkyl radical, or R18 and R19 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R14 represents a hydrogen atom, an alkyl radical or a xe2x80x94COR20 group,
R20 represents a hydrogen atom, an alkyl, alkoxy, aryl, aralkyl, heterocycloalkyl or xe2x80x94NR21R22 radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R21 and R22 represent, independently, a hydrogen atom or an alkyl radical, or R21 and R22 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
W represents a bond, O or S or also an xe2x80x94NR23 radical, in which R23 represents a hydrogen atom or an alkyl radical;
or an A2 radical 
xe2x80x83in which
R24, R25 and R26 represent, independently, a hydrogen, a halogen, the OH or SR27 group, an alkyl, alkenyl, alkoxy radical or an xe2x80x94NR28R29 radical,
R27 represents a hydrogen atom or an alkyl radical,
R28 and R29 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR30 group, or R28 and R29 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R30represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR31R32 radical,
R31 and R32 represent, independently, a hydrogen atom or an alkyl radical, or R31 and R32 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
Q represents xe2x80x94OR33, xe2x80x94SR33, xe2x80x94NR34R35 or an aryl radical substituted by one or more identical or different substituents chosen from: halogen, the OH group, an alkyl, alkoxy, cyano, nitro or xe2x80x94NR15R16 radical,
R33 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
R34 and R35 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COxe2x80x94R36 radical, or together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R36 representing an alkyl radical;
or an A3 radical 
in which R37 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or xe2x80x94NR4R5;
T represents a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2;
or an A4 radical 
in which R38 represents a hydrogen atom, an alkyl, xe2x80x94(CH2)qxe2x80x94NR39R40 or aralkyl radical, the aryl group being optionally substituted by one or more identical or different substituents chosen from: OH, alkyl, halogen, nitro, alkoxy or xe2x80x94NR39R40,
q being an integer comprised between 2 and 6;
or an A5 radical 
in which Rxe2x80x238 and Rxe2x80x338 represent independently a hydrogen atom, nitro, xe2x80x94NRxe2x80x239Rxe2x80x240, an alkyl or arylalkyl radical, the aryl group being optionally substituted by one or more identical or different substituents chosen from: OH, the alkyl, halogen, nitro, alkoxy or xe2x80x94NR39R40 radicals,
Rxe2x80x239, Rxe2x80x240, R39 and R40 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR41 group, or R39 and R40 or Rxe2x80x239 and Rxe2x80x240 together with the nitrogen atom form an optionally substituted heterocycle,
R41 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR42R43 radical,
R42 and R43 represent, independently, a hydrogen atom or an alkyl radical, or R42 and R43 together with the nitrogen atom to which they are .attached form an optionally substituted heterocycle,
T representing a xe2x80x94(CH2)mxe2x80x94 radical with m=1 or 2,
or finally an A6 radical 
in which R44 represents a hydrogen atom, the OH group or an alkyl or alkoxy radical;
Xa represents xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94(CH2)nxe2x80x94COxe2x80x94,xe2x80x94N(R45)xe2x80x94COxe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94NHxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94Sxe2x80x94(CH2)n,xe2x80x94COxe2x80x94 or xe2x80x94Zxe2x80x94COxe2x80x94;
D represents a phenylene radical optionally substituted by one or more identical or different radicals chosen from alkyl, alkoxy, OH, nitro, halogen, cyano, or carboxyl to optionally esterified by an alkyl radical;
Z represents a heterocycle,
R45 represents a hydrogen atom or an alkyl radical,
R46 and R47 represent, independently, a hydrogen atom, an alkyl, aryl or aralkyl radical the alkyl and aryl groups of which are optionally substituted by one or more identical or different substituents chosen from: the OH, xe2x80x94SH, halogen, nitro, alkyl, alkoxy, alkylthio, aralkoxy, aryl-alkylthio, xe2x80x94NR48R49 and carboxyl group optionally esterified by an alkyl radical;
R48 and R49 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR50 group, or R48 and R49 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R50 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR51R52 radical,
R51 and R52 represent, independently, a hydrogen atom or an alkyl radical, or R51 and R52 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle;
n being an integer comprised between 0 and 6;
Ya represents xe2x80x94(CH2)pxe2x80x94, xe2x80x94C(R53R54)xe2x80x94(CH2)pxe2x80x94, xe2x80x94C(R53R54)xe2x80x94COxe2x80x94;
R53 and R54 represent, independently, a hydrogen atom, an alkyl radical, an aralkyl radical the aryl group of which is optionally substituted by one or,more identical or different substituents chosen from: the OH group, halogen, nitro, alkyl, alkoxy, xe2x80x94NR55R56,
R55 and R56 represent, independently, a hydrogen atom, an alkyl radical or a xe2x80x94COR57 group, or R55 and R56 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R57 represents a hydrogen atom, an alkyl, alkoxy or xe2x80x94NR58R59 radical,
R58 and R59 represent, independently, a hydrogen atom or an alkyl radical, or R58 and R59 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle;
p being an integer comprised between 0 and 6;
Heta represents a heterocycle,
as well as addition salts with mineral and organic acids or with mineral and organic bases of said compounds of general formula (I),
for the preparation of medicaments for the treatment of pathologies where calpains and/or reactive oxygen species are involved.
A more particular subject of the invention is the use of compounds of formula (Ia) as defined above, for the preparation of medicaments for the treatment of pathologies involving reactive oxygen species. A more particular subject of the invention is also the use of compounds of formula (Ia) as defined above, for the preparation of medicaments for the treatment of pathologies involving reactive oxygen species and calpains. The invention therefore relates to the use of compounds of formula (Ia) as defined above, for the preparation of medicaments for the treatment of pathologies such as inflammatory and immunological diseases, cardiovascular and cerebrovascular diseases, disorders of the central or peripheral nervous system, osteoporosis, muscular dystrophy, proliferative diseases, cataracts, organ transplants, auto-immune and viral diseases, cancer, and all pathologies characterized by an excessive production of ROS""s and/or the activation of calpains.
A more particular subject of the invention is the use of compounds of formula (Ia) as defined above, characterized in that Het represents a monocyclic radical containing 1 to 2 heteroatoms chosen from O and N. Preferentially, Het represents tetrahydrofuran, dioxolane, pyrrolidine, 1,3-oxazolidine, and R1 represents the hydrogen atom, the xe2x80x94OR3 or oxo radical.
A more particular subject of the invention is the use of compounds of formula (Ia) as defined above, characterized in that X represents xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94N(R45)xe2x80x94Dxe2x80x94COxe2x80x94, xe2x80x94Zxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94C(R46R47)xe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94, xe2x80x94N(R45)xe2x80x94COxe2x80x94NHxe2x80x94C(R46R47)xe2x80x94COxe2x80x94 or xe2x80x94COxe2x80x94N(R45)xe2x80x94C(R46R47)xe2x80x94CO and preferentially when R45 and R47 represent the hydrogen atom, R46 represents the hydrogen atom, an alkyl or phenyl radical, D represents the phenylene radical and Z represents the thiazole radical.
A more particular subject of the invention is the use of compounds of formula (Ia) as defined above characterized in that R2 represents a hydrogen atom or an aralkyl radical, and preferably the benzyl radical.
A more particular subject of the invention is the use of compounds of formula (Ia) as defined above characterized in that A represents either A1 with W representing the sulphur atom; or Axe2x80x21; or A2 together with R24, R25 and R26 which represent, independently, a hydrogen or an alkyl radical and Q which represents xe2x80x94OR33; or A3 together with T representing the xe2x80x94(CH2)2xe2x80x94 radical; or A4 together with T representing the xe2x80x94(CH2)xe2x80x94 radical. Preferably, A represents a radical chosen from 
A more particular subject of the invention is also the use as defined above, of compounds of formula (Ia) as described in the examples and preferentially the compounds which correspond to one of the following formulae:
(2R)-6-hydroxy-N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;
N-1-(4-anilinophenyl)-N-4-[(3S)-2-hydroxytetrahydro-3-furanyl]succinamide;
(3S)-3-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}tetrahydro-2-furanyl acetate;
N-1-(4-anilinophenyl)-N-4-[(1S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl]succinamide;
N-1-(4-anilinophenyl)-N-3-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenylmalonamide;
3-(4-anilinoanilino)tetrahydro-2-furanol;
N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl acetate;
N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;
N-[4-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;
N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl pivalate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl 3,3-dimethylbutanoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl benzoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl phenylacetate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl (2S)-2-(dimethylamino)-3-phenylpropanoate;
(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl 4-morpholinecarboxylate;
N-{(1S)-3-methyl-1-[(3-oxo-1-pyrrolidinyl)carbonyl]butyl}-10H-phenothiazine-2-carboxamide;
2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]acetamide;
N1-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenyl-N3-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;
N-(2-anilinophenyl)-Nxe2x80x2-[(3S)-2-hydroxytetrahydro-3-furanyl]urea;
N1-[(3S)-2-hydroxytetrahydro-3-furanyl]-N2-(1-propyl-2,3-dihydro-1H-indol-5-yl)ethanediamide;
(2R)-N-[(1S)-1-(1,3-dioxolan-2-yl)-2-phenylethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;
N-[(3S)-2-hydroxytetrahydro-3-furanyl]-5-indolinecarboxamide.
The non-commercial synthesis intermediates of formula (II), (III) and (V) can be prepared according to the different synthesis routes below:
1) Synthesis of Intermediates (II)
The carboxylic acids of general formula (II), in which A, X, D, n, R45, R46 and R47 are as described above, are accessible from the following synthetic diagrams:
1.1) Starting from A-NH(R45)
The preparation of carboxylic acids of general formula (II) can be carried out, in this case, from 3 different acid-ester derivatives (II.2), (II.4) and (II.6):
The condensation of the anilines of general formula (II.1) with commercial acid-esters (Alk=Alkyl) of general formula (II.2), Diagram 1.1, is carried out by standard peptide condensation. The carboxarnide obtained intermediately (II.3) is then saponified in order to produce the carboxylic acids of general formula (II). The synthesis of the intermediates of general formula (II.1) is described below. 
The synthesis of the carboxylic acids of general formula (II) can also be carried out by condensation of the anilines of general formula (II.1) with the acid-ester derivatives of general formula (II.4) under the conditions described previously. This condensation is followed by standard saponification in order to produce acids of general formula (II). The synthesis of intermediates of general formula (II.4) is described below.
The condensation of the amines of general formula (II.1) with the commercial aromatic acids of general formula (II.6), under standard peptide synthesis conditions described already, after saponification of the intermediates of general formula (II.7) also leads to carboxylic acids of general formula (II).
Alternatively, the carboxylic acids of general formula (II) are also accessible by opening cyclic anhydrides such as for example succinic anhydride, using the amines of general formula (II.1) according to an experimental protocol described in the literature (J. Amer. Chem. Soc. (1951) 73, 4007).
1.1.1) Preparation of Intermediates (II.1)
The non-commercial anilines of general formula (II.1), derivatives of indoline or 1,2,3,4-tetrahydroquinoline, Diagram 1.1.1, in which T and R38 are as defined above, can be prepared from the corresponding nitro derivatives of general formula (II.1.1). 6-nitro-1,2,3,4-tetrahydroquinoline is described in Can. J. Chem. (1952), 30, 720-722. Alkylation of the amine is carried out in a standard fashion using a strong base such as, for example, NaH, in a polar aprotic solvent such as, for example, DMF in the presence of a halogenated derivative R38-Hal, such as for example 3-dimethylaminopropanol chloride or benzyl bromide. The nitro derivative of general formula (II.1.2) obtained intermediately is then reduced, for example, by Raney Nickel in the presence of hydrazine hydrate in order to produce the anilines of general formula (II.1). 
Moreover, certain non-commercial derivatives of phenylenediamines of general formula (II.1) can be prepared according to Farmaco (1951) 6,713-717.
In the particular case where A is a phenolic derivative (A=A2), the anilines of general formula (II.1) are obtained by hydrogenation, in the presence of Pd/C, of the nitrophenol derivative precursors. The nitrated derivatives of di-alkyl phenols are accessible according to the methods described in J. Org. Chem. (1968) 33 (1), 223-226 or J. Med. Chem. (1998), 41, 1846-1854.
The intermediates of general formula (II.1) in which Axe2x80x21 is a diphenylamine are accessible via the methods described in the literature (Synthesis (1990) 430; Indian J. Chem. (1981) 20B, 611-613; J. Med. Chem. (1975) 18 (4), 386-391) which involve the reduction of a nitrodiphenylamine intermediate. Reduction of the nitro function is carried out in a standard fashion by hydrogenation in the presence of a catalytic quantity of Pd/C in order to access the aminodiphenylamines of general formula (II.1).
When A is a carbazole derivative (W then represents a direct bond), the methods for preparing the aminocarbazoles of general formula (II.1) involve the synthesis of a nitrocarbazole intermediate. These methods are described in Pharmazie (1993) 48 (11), 817-820; Synth. Commun. (1994) 24(1), 1-10; J. Org. Chem. (1980),45, 1493-1496; J. Org. Chem. (1964) 29 (8), 2474-2476; Org. Prep. Proced. Int. (1981) 13 (6), 419-421 or J. Org. Chem. (1963) 28, 884. Reduction of the nitro function of the nitrocarbazole intermediates is, in this case, preferably carried out using hydrazine hydrate in the presence of Raney Nickel.
The intermediates of general formula (II.1) in which A is a phenothiazine derivative (W represents a sulphur atom), are accessible via methods in the literatures which involve the synthesis of a nitrophenothiazine derivative. In particular 3-nitrophenothiazine is described in J. Org. Chem. (1972) 37, 2691. The reduction of the nitro function in order to access the aminophenothiazines of general formula (II.1) is carried out in a standard fashion by hydrogenation in the presence of a catalytic quantity of Pd/C in a solvent such as ethanol.
1.1.2) Preparation of Intermediates (II.4)
The acid-esters of general formula (II.4), Diagram 1.1.2, can be prepared from the commercial diesters of general formula (II.4.1) according to a method described in the literature (Tetrahedron Asymmetry (1997) 8(11), 1821-1823). 
1.2) Starting from A-CO2H
The carboxylic acid intermediates of general formula (II) are also accessible via the condensation of the carboxylic acids of general formula (II.8) with the commercial amino-esters of general formula (II.9A) or (II.9B), Diagram 1.2, during a peptide synthesis stage described previously. The carboxamides obtained intermediately (II.10A) and (II.10B) are then saponified in order to produce the carboxylic acids of general formula (II). 
1.2.1) Preparation of Intermediates (II.8)
The carboxylic derivatives of general formula (II.8), which are not commercially accessible, can be prepared from the literature (e.g.: J. Org. Chem. (1961) 26, 1221-1223; Acta Chem. Scandinavica (1973) 27, 888-890; Can. J. Chem. (1972),50, 1276-1282; J. Med. Chem. (1992) 35(4), 716-724; J. Org. Chem. (1989) 54, 560-569; J. Med. Chem. (1998) 41(2), 148-156; Bull. Soc. Chim. Fr. (1960), 1049-1066)).
1.3) Starting from A-OH or A-SH
The acids of general formula (II) (Diagram 1.3) in which X represents xe2x80x94Oxe2x80x94(CH2)nxe2x80x94COxe2x80x94, are prepared from the hydroquinones of general formula (II.11) obtained according to the literature (J. Chem. Soc. Perkin 1 (1981) 303-306). The condensation on commercial halogen esters of general formula (II.12) is carried out in the presence of a base such as, for example K2CO3, by heating in a polar solvent such as, for example, THF for at least 5 hours. The esters of general formula (II.13) intermediately obtained are then deprotected (in an acid medium in the case of tert-butyl esters) in order to produce acids of general formula (II). 
The acids of general formula (II) in which X represents xe2x80x94Sxe2x80x94(CH2)nxe2x80x94COxe2x80x94, are prepared according to a method in the literature (J. Med. Chem. (1997) 40(12), 1906-1918).
1.4) Starting from A-CO2H, when Z represents a heterocycle with V=S or O
1.4.a) In the case where Z represents an unsaturated heterocycle, the carboxylic acids of general formula (II), Diagram 1.4a, can be prepared from carboxylic acids of general formula (II.8). 
The formation of the primary carboxamide of general formula (II.14) is carried out according to an experimental protocol described in the literature (Synthesis (1989), 1, 37). By heating, between 50xc2x0 C. and reflux of the solvent, for a time comprised between 1 and 15 hours, intermediate (II.14) in the presence of an alkyl bromopyruvate, the oxazoles (V xe2x95x90O) of general formula (II.16) are obtained. Alternatively, the thiazoles (Vxe2x95x90S) of general formula (II.16), are accessible in two stages from the carboxamides of general formula (II.14). These, in the presence of Lawesson""s reagent in a solvent such as, for example, 1,4-dioxane, lead in a standard fashion to the thiocarboxamides of general formula (II.15). The cyclization stage is then carried out in the presence of alkyl bromopyruvate as described previously. The carboxylic acids of general formula (II) are finally obtained by deprotection of the acid function under standard conditions.
1.4.b) In the case where Z represents a saturated heterocycle, and in particular a thiazolidine, the carboxylic acids of general formula (II), Diagram 1.4b, are also accessible from the carboxylic acids of general formula (II.8). 
The preparation of the aldehydes of general formula (II.17) is carried out in a standard fashion after activation of the acid function of the intermediates of general formula (II.8) in the form of an ester or an alkylhydroxamate, in the presence of DIBAL or of LiAlH4, according to the experimental protocols in the literature (e.g. J. Med. :Chem. (1990) 33, 11-13). The reaction of these aldehydes with cysteine in the presence of acetate salts leads directly to the thiazolidines of general formula (II.18) according to an experimental protocol described in J. Org. Chem. (1957) 22, 943-946. The amine of the thiazolidine ring is then protected in the form of a carbamate (e.g. Boc) under standard conditions in the literature in order to produce the carboxylic acids of general formula (II).
1.5) Starting from A-N(R45)xe2x80x94COxe2x80x94
The carboxylic acids of general formula (II), in which X=xe2x80x94N(R45)xe2x80x94(CH2)nxe2x80x94COxe2x80x94 with n=0, are constituted by a chain functionalized by a urea, Diagram 1.5. 
The synthesis of these ureas is carried out by condensation of the amines of general formula (II.1) with the aminoesters of general formula (II.9) in the presence of triphosgene and a tertiary amine according to an experimental protocol described in the literature (J. Org. Chem. (1994), 59(7), 1937-1938) in order to produce the intermediates of general formula (II.19). The carboxylic acid of general formula (II) is then obtained in a standard fashion by deprotection of the intermediate ester.
2) Synthesis of Intermediates (III)
The preparation of intermediates of general formula (III), Diagram 1.4, in which R2 is as defined above and Y=xe2x80x94(CH2)pxe2x80x94, with p=0, is carried out from derivatives of N-Cbz aspartic acid of general formula (III.1) access to which is described in the literature (J. Med. Chem. (1973) 16(11), 1277-1280). By heating these intermediates in the presence of trioxane and a catalytic quantity of PTSA under reflux of a solvent such as, for example, toluene, (Synthesis (1989) 7, 542-544) the oxazolidinone derivatives of general formula (III.2) are obtained. Reduction of the acid function is then carried out using B2H6.THF in THF as described in Chem. Pharm. Bull. (1995) 43 (10), 1683-1691 and leads to alcohols of general formula (III.3). These are then treated in a basic medium, and intermediate (III.4) generated in this way is cyclized using a standard dehydration agent such as, for example, dicyclohexylcarbodiimide in order to obtain the substituted lactone of general formula (III.5). The intermediate of general formula (III) is obtained after cleavage of the benzyl carbamate using Pd/C under a hydrogen atmosphere. 
3) Synthesis of Intermediates (V)
The intermediates of general formula (V) (Diagram 2.1), in which A, X, Y, R53 and R54 are as described above, are prepared in a standard fashion by peptide condensation of the acids of general formula (II), described previously, with commercial amino-esters of general formula (V.1). Carboxylic acids of general formula (V) are obtained after saponification of the intermediate esters of general formula (V.2). 
A subject of the invention is also, as new industrial products, and in particular as new industrial products intended for the preparation of products of formula I, the products corresponding to one of the following formulae:
N-1-(4-anilinophenyl)-N-4-[(3S)-2-oxotetrahydro-3-furanyl]succinamide;
methyl (2S)-2-{([4-(4-anilinoanilino)-4-oxobutanoyl]amino}-4-methylpentanoate;
N1-(4-anilinophenyl)-N4-[(1S)-1-formyl-3-methylbutyl]succinamide;
benzyl 3-(4-anilinoanilino)-3-oxo-2-phenylpropanoate;
3-(4-anilinoanilino)-3-oxo-2-phenylpropanoic acid;
N-1-(4-anilinophenyl)-N-3-[(3S)-2-oxotetrahydro-3-furanyl]-2-phenylmalonamide;
3-(4-anilinoanilino)dihydro-2(3H)-furanone;
methyl (2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoate;
(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoic acid;
N-[(1S)-3-methyl-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)butyl]-10H-phenothiazine-2-carboxamide;
ethyl 2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylate;
2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylic acid;
N-[(3S)-2-oxotetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;
methyl 4-[(10H-phenothiazin-2-ylcarbonyl)amino]benzoate;
4-[(10H-phenothiazin-2-ylcarbonyl)amino]benzoic acid;
N-[4-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;
methyl (2S)-4-methyl-2-[(10H-phenothiazin-1-ylcarbonyl)amino]pentanoate;
(2S)-4-methyl-2-[(10H-phenothiazin-1-ylcarbonyl)amino]pentanoic acid;
N-[(1S)-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;
N-[(1S)-1-(1,4-dioxa-7-azaspiro[4.4]non-7-ylcarbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;
2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-oxotetrahydro-3-furanyl]acetamide
5-nitro-1-propylindoline;
1-propyl-2,3-dihydro-1H-indol-5-ylamine;
3-oxo-2-phenyl-N-(1-propyl-2,3-dihydro-1H-indol-5-yl)-beta-alanine;
N1-[(3S)-2-oxotetrahydro-3-furanyl]-2-phenyl-N3-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;
N-(2-anilinophenyl)-Nxe2x80x2-[(3S)-2-oxotetrahydro-3-furanyl]urea;
ethyl oxo[(1-propyl-2,3-dihydro-1H-indol-5-yl)amino]acetate;
oxo[(1-propyl-2,3-dihydro-1H-indol-5-yl)amino]acetic acid;
methyl (2S)-2-({[(2R)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]carbonyl}amino)-3-phenylpropanoate;
(2R)-N-[(1S)-1-benzyl-2-oxoethyl]-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;
tert-butyl5-methyl 1,5-indolinedicarboxylate;
1-(tert-butoxycarbonyl)-5-indolinecarboxylic acid;
tert-butyl 5-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)-1-indolinecarboxylate;
tert-butyl 5-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-1-indolinecarboxylate.
Experimental Part
The following examples are presented in order to illustrate the above procedures and should in no event be considered as a limit to the scope of the invention.